Pyruvate kinase activators for use in therapy

ABSTRACT

Described herein are methods for using compounds that activate pyruvate kinase.

This application is a continuation of U.S. Ser. No. 14/886,750, filedOct. 19, 2015 and published as U.S. Pat. No. 9,682,080, which is acontinuation of U.S. Ser. No. 14/115,289, filed Feb. 11, 2014 andpublished as U.S. Pat. No. 9,193,701, which is a national stageapplication under 35 U.S.C. § 371 of International Application No.PCT/US2012/036412, filed May 3, 2012, and published as InternationalPublication No. WO 2012/151451 on Nov. 8, 2012, which claims priorityfrom U.S. Ser. No. 61/482,171, filed May 3, 2011, the contents of eachof which is incorporated herein by reference in its entirety.

Pyruvate kinase deficiency (PKD) is one of the most common enzymedefects in erythrocytes in human due to autosomal recessive mutations ofthe PKLR gene (Zanella, A., et al., Br J Haematol 2005, 130 (1), 11-25).It is also the most frequent enzyme mutation in the central glycolyticpathway and only second to glucose-6 phosphate dehydrogenase (G6PD)deficiency (Kedar, P., et al., Clin Genet 2009, 75 (2), 157-62) of thehexose monophosphate shunt.

Human erythrocytes are unique in that they anucleate when mature.Immature erythocytes have nuclei but during early erythropoiesis priorto becoming circulating reticulocytes they extrude nuclei as well asother organelles such as mitochondria, endoplasmic reticulum, and golgiapparatus, in order to make room for oxygen-carrying hemoglobin. As aresult of lacking mitochondria, mature red blood cells do not utilizeany of the oxygen they transport to economically synthesize adenosinetriphosphate (ATP) as other normal differentiated cells do. Instead, redblood cells depend entirely on anaerobic glycolysis to cyclenicotinamide adenine dinucleotide (NAD⁺) and to make ATP, an essentialenergy source largely used to drive ATPase-dependent K+/Na⁺ and Ca²⁺pumps, in order to maintain cell membrane integrity and pliability asthey navigate through blood vessels. In PKD disorder, two majordistinctive metabolic abnormalities are ATP depletion and concomitantincrease of 2,3-diphosphoglycerate consistent with accumulation of upperglycolytic intermediates. Moreover, one of the consequences of decreasedATP and pyruvate level is lowered lactate level leading to inability toregenerate NAD⁺ through lactate dehydrogenase for further use inglycolysis. The lack of ATP disturbs the cation gradient across the redcell membrane, causing the loss of potassium and water, which causescell dehydration, contraction, and crenation, and leads to prematuredestruction and diminished lifetime of the red blood cells (RBCs). Suchdefective RBCs are destroyed in the spleen, and excessive hemolysis ratein the spleen leads to the manifestation of hemolytic anemia. The exactmechanism by which PKD sequesters newly matured RBCs in the spleen toeffectively shorten overall half-lives of circulating RBCs is not yetclear, but recent studies suggest that metabolic dysregulation affectsnot only cell survival but also the maturation process resulting inineffective erythropoiesis (Aizawa, S. et al., Exp Hematol 2005, 33(11), 1292-8).

Pyruvate kinase catalyzes the transfer of a phosphoryl group fromphosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate andone molecule of ATP. The enzyme has an absolute requirement for Mg²⁺ andK⁺ cations to drive catalysis. PK functions as the last critical step inglycolysis because it is an essentially irreversible reaction underphysiological conditions. In addition to its role of synthesizing one ofthe two ATP molecules from the metabolism of glucose to pyruvate,pyruvate kinase is also an important cellular metabolism regulator. Itcontrols the carbon flux in lower-glycolysis to provide key metaboliteintermediates to feed biosynthetic processes, such as pentose-phosphatepathway among others, in maintaining healthy cellular metabolism.Because of these critical functions, pyruvate kinase is tightlycontrolled at both gene expression and enzymatic allostere levels. Inmammals, fully activated pyruvate kinase exists as a tetrameric enzyme.Four different isozymes (M1, M2, L and R) are expressed from twoseparate genes. Erythrocyte-specific isozyme PKR is expressed from thePKLR gene (“L gene”) located on chromosome 1q21. This same gene alsoencodes the PKL isozyme, which is predominately expressed in the liver.PKLR consists of 12 exons with exon 1 is erythroid-specific whereas exon2 is liver-specific. The two other mammalian isozymes PKM1 and PKM2 areproduced from the PKM gene (“M gene”) by alternative splicing eventscontrolled by hnRNP proteins. The PKM2 isozyme is expressed in fetaltissues and in adult proliferating cells such as cancer cells. Both PKRand PKM2 are in fact expressed in proerythroblasts. However, uponerythroid differentiation and maturation, PKM2 gradually is decreased inexpression and progressively replaced by PKR in mature erythrocytes.

Clinically, hereditary PKR deficiency disorder manifests asnon-spherocytic hemolytic anemia. The clinical severity of this disorderrange from no observable symptoms in fully-compensated hemolysis topotentially fatal severe anemia requiring chronic transfusions and/orsplenectomy at early development or during physiological stress orserious infections. Most affected individuals who are asymptomatic,paradoxically due to enhanced oxygen-transfer capacity, do not requireany treatment. However, for some of the most severe cases, whileextremely rare population-wise with estimated prevalence of 51 permillion (Beutler, E. Blood 2000, 95 (11), 3585-8), there is nodisease-modifying treatment available for these patients other thanpalliative care (Tavazzi, D. et al., Pediatr Ann 2008, 37 (5), 303-10).These hereditary non-spherocytic hemolytic anemia (HNSHA) patientspresent a clear unmet medical need.

Heterogenous genetic mutations in PKR lead to dysregulation of itscatalytic activity. Since the initial cloning of PKR and report of asingle point mutation Thr³⁸⁴>Met associated with a HNSHA patient (Kanno,H. et al., Proc Natl Acad Sci USA 1991, 88 (18), 8218-21), there are nownearly 200 different reported mutations associated with this diseasereported worldwide (Zanella, A. et al., Br J Haematol 2005, 130 (1),11-25; Kedar, P., et al., Clin Genet 2009, 75 (2), 157-62; Fermo, E. etal., Br J Haematol 2005, 129 (6), 839-46; Pissard, S. et al., Br JHaematol 2006, 133 (6), 683-9). Although these mutations represent widerange genetic lesions that include deletional and transcriptional ortranslational abnormalities, by far the most common type is missensemutation in the coding region that one way or another affects conservedresidues within domains that are structurally important for optimalcatalytic function of PKR. The pattern of mutation prevalence seems tobe unevenly distributed toward specific ethnic backgrounds. Forinstance, the most frequent codon substitutions reported for NorthAmerican and European patients appear to be Arg⁴⁸⁶>Trp and Arg⁵¹⁰>Gln,while mutations Arg⁴⁷⁹>His, Arg⁴⁹⁰>Trp and Asp³³¹>Gly were morefrequently found in Asian patients (Kedar, P., et al., Clin Genet 2009,75 (2), 157-62).

The present invention provides a method for increasing lifetime of thered blood cells (RBCs) in need thereof comprising contacting blood withan effective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt thereof; (2) a composition comprising acompound disclosed herein or a salt thereof and a carrier; or (3) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention further provides a method for regulating2,3-diphosphoglycerate levels in blood in need thereof comprisingcontacting blood with an effective amount of (1) a compound disclosedherein or a pharmaceutically acceptable salt thereof; (2) a compositioncomprising a compound disclosed herein or a salt thereof and a carrier;or (3) a pharmaceutical composition comprising a compound disclosedherein or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The present invention also provides a method for treating hereditarynon-spherocytic hemolytic anemia comprising administering to a subjectin need thereof a therapeutically effective amount of (1) a compounddisclosed herein or a pharmaceutically acceptable salt thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention further provides a method for treating sickle cellanemia comprising administering to a subject in need thereof atherapeutically effective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt thereof; (2) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating hemolyticanemia (e.g., chronic hemolytic anemia caused by phosphoglycerate kinasedeficiency, Blood Cells Mol Dis, 2011; 46(3):206) comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (1) a compound disclosed herein or a pharmaceuticallyacceptable salt thereof; (2) a pharmaceutical composition comprising acompound disclosed herein or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating thalassemia(e.g., beta-thalassemia), hereditary spherocytosis, hereditaryelliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome),paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g.,congenital anemias (e.g., enzymopathies)), or anemia of chronic diseasescomprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt thereof; (2) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating diseases orconditions that are associated with increased 2,3-diphosphoglyceratelevels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283) andParkinson's (J. Neurol, Neurosurg, and Psychiatry 1976, 39:952)comprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt thereof; (2) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Compounds and compositions described herein are activators of PKRmutants having lower activities compared to the wild type, thus areuseful for methods of the present invention. Such mutations in PKR canaffect enzyme activity (catalytic efficiency), regulatory properties(modulation by fructose bisphosphate (FBP)/ATP), and/or thermostabilityof the enzyme. Examples of such mutations are described in Valentini etal, JBC 2002. Some examples of the mutants that are activated by thecompounds described herein include G332S, G364D, T384M, G37E, R479H,R479K, R486W, R532W, R510Q, and R490W. Without being bound by theory,compounds described herein affect the activities of PKR mutants byactivating FBP non-responsive PKR mutants, restoring thermostability tomutants with decreased stability, or restoring catalytic efficiency toimpaired mutants. The activating activity of the present compoundsagainst PKR mutants may be tested following a method described inExample 1. Compounds described herein are also activators of wild typePKR.

In an embodiment, to increase the lifetime of the red blood cells, acompound, composition or pharmaceutical composition described herein isadded directly to whole blood or packed cells extracorporeally or beprovided to the subject (e.g., the patient) directly (e.g., by i.p.,i.v., i.m., oral, inhalation (aerosolized delivery), transdermal,sublingual and other delivery routes). Without being bound by theory,compounds described herein increase the lifetime of the RBCs, thuscounteract aging of stored blood, by impacting the rate of release of2,3-DPG from the blood. A decrease in the level of 2, 3-DPGconcentration induces a leftward shift of the oxygen-hemoglobindissociation curve and shifts the allosteric equilibribrium to the R, oroxygenated state, thus producing a therapeutic inhibition of theintracellular polymerization that underlies sickling by increasingoxygen affinity due to the 2,3-DPG depletion, thereby stabilizing themore soluble oxy-hemoglobin. Accordingly, in one embodiment, compoundsand pharmaceutical compositions described herein are useful asantisickling agents. In another embodiment, to regulate2,3-diphosphoglycerate, a compound, composition or pharmaceuticalcomposition described herein is added directly to whole blood or packedcells extracorporeally or be provided to the subject (e.g., the patient)directly (e.g., by i.p., i.v., i.m., oral, inhalation (aerosolizeddelivery), transdermal, sublingual and other delivery routes).

In one embodiment, provided is a pharmaceutical composition comprising acompound or a pharmaceutically acceptable salt of formula (I):

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)—C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)— (wherein the point of the attachment to R¹ is on theleft-hand side);

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, haloalkoxy,alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a),—C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) takentogether with the carbon atoms to which they are attached form anoptionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 represents a table of exemplary compounds.

The details of construction and the arrangement of components set forthin the following description or illustrated in the drawings are notmeant to be limiting. Embodiments can be practiced or carried out invarious ways. Also, the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having,” “containing”,“involving”, and variations thereof herein, is meant to encompass theitems listed thereafter and equivalents thereof as well as additionalitems.

Compounds

Described herein are compounds and compositions that activate wild typePKR and/or various mutant PKRs such as those described herein.

In one embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)—C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)— (wherein the point of the attachment to R¹ is on theleft-hand side);

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;

each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, haloalkoxy,alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a),—C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) takentogether with the carbon atoms to which they are attached form anoptionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2.

In certain embodiments, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted bicyclic heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)—C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)—;

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a) or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted cyclyl; eachR^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, haloalkoxy,alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a),—C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) takentogether with the carbon atoms to which they are attached form anoptionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2. In some embodiments, h is 1. In some embodiments, h is2.

In some embodiments, g is 1. In some embodiments, g is 2.

In some embodiments, both h and g are 1. In some embodiments, h is 1 andg is 2. In some embodiments, g is 1 and h is 2.

In some embodiments, W, X, Y and Z are CH. In some embodiments, at leastone of W, X, Y and Z is N. In some embodiments, at least two of W, X, Yand Z are N. In some embodiments, at least three of W, X, Y and Z are N.

In some embodiments, W, X, Y, Z and the carbons to which they areattached form a pyridyl ring. In some embodiments, W, X, Y, Z and thecarbon atoms to which they are attached form a pyrimidyl ring. In someembodiments, W, X, Y, Z and the carbon atoms to which they are attachedform a pyridazinyl ring.

In some embodiments, W, X and Y are CH and Z is N.

In some embodiments, X, Y and Z are CH and W is N.

In some embodiments, D is NR^(b) and D¹ is a bond. In some embodiments,D is a bond and D¹ is NR^(b). In some embodiments, both D and D¹ areNR^(b). In some embodiments, R^(b) is alkyl (e.g., methyl or ethyl). Insome embodiments, R^(b) is hydrogen (H).

In some embodiments, A is a 9-10 membered bicyclic heteroaryl (e.g.,quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, indolyl,benzoxazolyl, pyrrolopyridyl, pyrrolopyrimidyl, benzimidazolyl,benzthiazolyl, or benzoxazolyl). In some embodiments, A is aN-containing 9-10 membered bicyclic heteroaryl. In some embodiments, Ais optionally substituted quinazolinyl (e.g., 8-quinazolinyl or4-quinazolinyl), optionally substituted quinoxalinyl (e.g.,5-quinoxalinyl), optionally substituted quinolinyl (e.g., 4-quinolinylor 8-quinolinyl), optionally substituted cinnolinyl (e.g.,8-cinnolinyl), optionally substituted isoquinolinyl, optionallysubstituted indolyl (7-indolyl), optionally substituted benzoxazolyl(e.g., 7-benzoxazolyl), optionally substituted pyrrolopyridyl (e.g.,4-pyrrolopyridyl), optionally substituted pyrrolopyrimidyl (e.g.,4-pyrrolopyrimidyl), optionally substituted benzimidazolyl (e.g.,7-benzimidazolyl), optionally substituted benzthiazolyl (e.g.,4-benzthiazolyl, 2-methyl-4-benzthiazolyl or 7-benzthiazolyl), oroptionally substituted benzoxazolyl (e.g., 4-benzoxazolyl). In someembodiments, A is optionally substituted with halo. In some embodiments,A is

In some embodiments, A is

In some embodiments, A is optionally substituted

In some embodiments, A is

In some embodiments, L is a bond.

In some embodiments, L is —(CR^(c)R^(c))_(m)— and m is 1. In someaspects of these embodiments, each R^(c) is hydrogen. In some aspects ofthese embodiments, one R^(c) is alkyl (e.g., methyl or ethyl) and theother R^(c) is hydrogen. In some aspects of these embodiments, one R^(c)is halo (e.g., fluoro) and one R^(c) is hydrogen. In some aspects ofthese embodiments, both R^(c) are halo (e.g., fluoro). In some aspectsof these embodiments, one R^(c) is alkoxy (e.g., methoxy or ethoxy) andone R^(c) is hydrogen. In some aspects of these embodiments, both R^(c)are alkoxy (e.g., methoxy or ethoxy). In some aspects of theseembodiments, two R^(c) taken together with the carbon to which they areattached form a cycloalkyl (e.g., cyclopropyl).

In some embodiments, L is —(CR^(c)R^(c))_(m)— and m is 2. In someaspects of these embodiments, each R^(c) is hydrogen. In some aspects ofthese embodiments, 1 R^(c) is alkyl (e.g., methyl or ethyl) and each ofthe other R^(c) are hydrogen. In some aspects of these embodiments, twoR^(c)s taken together with the carbon to which they are attached form acycloalkyl (e.g., cyclopropyl) and each of the other two R^(c)s arehydrogen.

In some embodiments, L is —(CR^(c)R^(c))_(m)— and m is 3. In someaspects of these embodiments each R^(c) is hydrogen.

In some embodiments, L is —C(O)—.

In some embodiments, L is —O—C(O)—.

In some embodiments, L is NR^(b)C(O)— and R^(b) is H. In someembodiments, L is NR^(b)C(S)— and R^(b) is H.

In some embodiments, L is —(CR^(c)R^(c))_(m)—C(O)— and m is 1. In someaspects of these embodiments, each R^(c) is hydrogen. In some aspects ofthese embodiments, one R^(c) is alkyl (e.g., methyl or ethyl) and oneR^(c) is hydrogen. In some aspects of these embodiments, both R^(c) arealkyl (e.g., methyl or ethyl).

In some embodiments, L is —(CR^(c)R^(c))_(m)—C(O)— and m is 2. In someaspects of these embodiments, each R^(c) is hydrogen.

In some embodiments, L is —(CR^(c)R^(c))_(m)—C(O)— and m is 3. In someaspects of these embodiments, each R^(c) is hydrogen.

In some embodiments, R¹ is alkyl substituted with 0-5 occurrences ofR^(d) (e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, n-propyl, i-propyl, or n-butyl. Insome embodiments, R¹ is ethyl or propyl (n-propyl or i-propyl). In someaspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—. Insome aspects of these embodiments, L is —O(CO)—.

In some embodiments, R¹ is alkyl substituted with 1 occurrence of R^(d)(e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, or n-propyl substituted with 1occurrence of R^(d). In some aspects of these embodiments, R^(d) is halo(e.g., fluorine or chlorine). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(a) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments, Lis —NHC(O)—.

In some embodiments, R¹ is alkyl substituted with 2 occurrences of R^(d)(e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, or n-propyl substituted with 2occurrences of R^(d). In some embodiments, R¹ is n-propyl substitutedwith 2 occurrences of R^(d). In some aspects of these embodiments, 1R^(d) is cyano and the other R^(d) is —NR^(a)R^(b). In some aspects ofthese embodiments, R^(a) and R^(b) are hydrogen. In some aspects ofthese embodiments, L is —CH₂—.

In some embodiments, R¹ is heteroaryl substituted with 0-5 occurrencesof R^(d) (e.g., S-containing monocyclic heteroaryl, N-containingmonocyclic heteroaryl or N-containing bicyclic heteroaryl). In someembodiments, R¹ is a 5-8 membered monocyclic heteroaryl substituted with0-5 occurrences of R^(d) (e.g., thiophenyl, pyridyl, pyrimidyl orpyrazyl). In some embodiments, R¹ is pyridyl substituted with 0-5occurrences of R^(d) (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl),pyrimidyl substituted with 0-5 occurrences of R^(d) (e.g., 2-pyrimidylor 5-pyrimidyl) or pyrazinyl substituted with 0-5 occurrences of R^(d)(e.g., 2-pyrazinyl). In some embodiments, R¹ is thiazolyl substitutedwith 0-5 occurrences of R^(d) (e.g., 2-thiazolyl or 5-thiazolyl). Insome embodiments, R¹ is pyrimidyl substituted with 0-5 occurrences ofR^(d) (e.g., 2-pyrimidyl). In some embodiments, R¹ is thiadiazolylsubstituted with 0-5 occurrences of R^(d) (e.g., 4-thiadiazolyl). Insome embodiments, R¹ is pyrrolyl substituted with 0-5 occurrences ofR^(d) (e.g., 2-pyrrolyl). In some aspects of these embodiments, L is abond, —CH₂—, —C(O)—, or —O(CO)—. In some embodiments, R¹ is pyridyl(e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl).

In some embodiments, R¹ is pyridyl (e.g., 2-pyridyl, 3-pyridyl or4-pyridyl) substituted with 1 occurrence of R^(d). In some aspects ofthese embodiments, R^(d) is —OC(O)R^(a). In some aspects of theseembodiments, R^(d) is —OR^(a). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(d) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments,R^(d) is haloalkyl (e.g., trifluoromethyl). In some aspects of theseembodiments, R^(d) is halo (e.g., fluorine or chlorine). In some aspectsof these embodiments, R^(a) is alkyl (e.g., methyl or ethyl). In someaspects of these embodiments, L is —CH₂—. In some embodiments, R¹ ispyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl) substituted with 2occurrences of R^(d). In some aspects of these embodiments, one R^(d) is—C(O)OR^(a) and the other R^(d) is —OR^(a). In some aspects of theseembodiments, R^(a) is alkyl (e.g., methyl or ethyl). In some aspects ofthese embodiments, both R^(d) are halo (e.g., fluoro or chloro). In someaspects of these embodiments, L is —CH₂—.

In some embodiments, R¹ is pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl).In some aspects of these embodiments, L is a bond.

In some embodiments, R¹ is pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl)substituted with 1 occurrence of R^(d). In some aspects of theseembodiments, R^(d) is halo (e.g., fluoro or chloro).

In some embodiments, R¹ is pyrazinyl (e.g., 2-pyrazinyl). In someaspects of these embodiments, L is a bond.

In some embodiments, R¹ is thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, or5-thiazolyl). In some aspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, or5-thiazolyl) substituted with 1 occurrences of R^(d). In some aspects ofthese embodiments, R^(d) is alkyl (e.g, methyl or ethyl). In someaspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is thiophenyl substituted with 0-5 occurrencesof R^(d) (e.g., 2-thiophenyl). In some embodiments, R¹ is thiophenyl.

In some embodiments, R¹ is thiadiazolyl (e.g., 4-thiadiazolyl).

In some embodiments, R¹ is pyrrolyl (e.g., 2-pyrrolyl).

In some embodiments, R¹ is cycloalkyl substituted with 0-5 occurrencesof R^(d) (e.g., cyclopropyl, cyclopentyl or cyclohexyl). In someembodiments, R¹ is cyclopropyl. In some embodiments, R¹ is cyclohexyl.In some embodiments, R¹ is cyclopentyl. In some aspect of theseembodiments, L is —CH₂—C(O)—. In some embodiment, R¹ is aryl substitutedwith 0-5 occurrences of R^(d). In some aspects of these embodiments, Lis a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments R¹ is aryl (e.g., phenyl). In some embodiments, R¹is phenyl. In some aspects of these embodiments, L is a bond, —CH₂—,—C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 1 occurrence ofR^(d). In some aspects of these embodiments, R^(d) is ortho substituted.In some aspects of these embodiments, R^(d) is meta substituted. In someaspects of these embodiments, R^(d) is para substituted. In some aspectsof these embodiments, R^(d) is halo (e.g., fluorine, bromine orchlorine). In some aspects of these embodiments, R^(d) is alkyl (e.g.,methyl, ethyl, isopropyl, t-butyl, n-butyl or n-pentyl). In some aspectsof these embodiments, R^(d) is haloalkyl (e.g., trifluoromethyl). Insome aspects of these embodiments, R^(d) is —OR^(a). In some aspects ofthese embodiments, R^(d) is —C(O)R^(a). In some aspects of theseembodiments, R^(d) is —SR^(a). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(d) iscyano. In some aspects of these embodiments, R^(d) is —NR^(a)R^(b). Insome aspects of these embodiments, R^(d) is haloalkoxy (e.g.,difluoromethoxy or trifluoromethoxy). In some aspects of theseembodiments, R^(d) is hydroxyl. In some aspects of these embodiments,R^(d) is —OC(O)R^(a). In some aspects of these embodiments, R^(d) isalkynyl (e.g., 1-hexynyl). In some aspects of these embodiments, R^(d)is haloalkyl (e.g., trifluoromethyl). In some aspects of theseembodiments, R^(a) is alkyl (e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl or n-pentyl). In some aspects of theseembodiments, R^(a) is hydroxyalkyl (e.g., 2-hydroxylethyl). In someaspects of these embodiments, R^(a) and R^(b) are alkyl (e.g., methyl orethyl). In some aspects of these embodiments, R^(a) is acyl (e.g.,acetyl) and R^(b) is hydrogen. In some aspects of these embodiments, Lis a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 2 occurrences ofR^(d). In some aspects of these embodiments, both R^(d) are halo (e.g.,fluorine or chlorine). In some aspects of these embodiments, both R^(d)are alkyl (e.g., methyl or ethyl). In some aspects of these embodiments,1 R^(d) is alkyl (e.g., methyl or ethyl) and the other is —OR^(a). Insome aspects of these embodiments, 1 R^(d) is halo (e.g., fluorine orchlorine) and the other R^(d) is —OR^(a). In some aspects of theseembodiments, both R^(d) are —OR^(a). In some aspects of theseembodiments, 1R^(d) is halo (e.g., fluorine or chlorine) and the otherR^(d) is hydroxyl. In some aspects of these embodiments, 1 R^(d) is halo(e.g., fluorine or chlorine) and the other is haloalkyl (e.g.,trifluoromethyl). In some aspects of these embodiments, 1 R^(d) is—OR^(a) and the other R^(d) is —C(O)OR^(a). In some aspects of theseembodiments, 1 R^(d) is —OR^(a) and the other R^(d) is hydroxyl. In someaspects of these embodiments, 1 R^(d) is alkyl (e.g., methyl or ethyl)and the other R^(d) is hydroxyl. In some aspects of these embodiments,both R^(d) are hydroxyl. In some aspects of these embodiments, 1 R^(d)is halo (e.g., fluorine) and the other R^(d) is haloalkyl (e.g.,trifluoromethyl). In some aspects of these embodiments, both R^(d) arehydroxyl. In some aspects of these embodiments, one R^(d) is haloalkyl(e.g., trifluoromethyl) and the other R^(d) is alkyl (e.g., methyl). Insome aspects of these embodiments, two R^(d), together with the carbonatoms to which they are attached, form an optionally substitutedheterocyclyl. In some aspects of these embodiments, two R^(d), togetherwith the carbon atoms to which they are attached, form an optionallysubstituted 5-7 membered heterocyclyl. In some aspects of theseembodiments, two R^(d), together with the phenyl ring to which they areattached, form the following structure:

In some aspects of these embodiments, R^(a) is alkyl (e.g., methyl orethyl). In some aspects of these embodiments, L is a bond, —CH₂—,—C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 3 occurrences ofR^(d). In some aspects of these embodiments, 3 R^(d) are halo (e.g.,fluorine or chlorine). In some aspects of these embodiments, 2 R^(d) arehalo (e.g., fluorine or chlorine) and 1 R^(d) is hydroxyl. In someaspects of these embodiments, 1 R^(d) is halo (e.g., fluorine orchlorine), 1 R^(d) is alkyl (e.g., methyl) and 1 R^(d) is hydroxyl. Insome aspects of these embodiments, 3 R^(d) are alkyl (e.g., methyl orethyl). In some aspects of these embodiments, 2 R^(d) are alkyl (e.g.,methyl or ethyl) and 1 R^(d) is hydroxyl. In some aspects of theseembodiments, 2 R^(d) are halo (e.g., fluorine or chlorine) and 1 R^(d)is —OR^(a). In some aspects of these embodiments, R^(a) is alkyl (e.g.,methyl or ethyl). In some aspects of these embodiments, 1 R^(d) ishydroxyl and 2 R^(d) are —OR^(a). In some aspects of these embodiments,R^(a) is alkyl (e.g., methyl or ethyl). In some aspects of theseembodiments, 3 R^(d) are —OR^(a). In some aspects of these embodiments,3 R^(d) are halo (e.g., fluorine or chlorine). In some aspects of theseembodiments, R^(a) is alkyl (e.g., methyl or ethyl). In some aspects ofthese embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 4 occurrences ofR^(d). In some aspects of these embodiments, 1 R^(d) is hydroxyl, 1R^(d) is alkyl (e.g., methyl or ethyl) and 2 R^(d) are —OR^(a). In someaspects of these embodiments, R^(a) is alkyl (e.g., methyl or ethyl). Insome aspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or—O(CO)—.

In some embodiments, R¹ is heterocyclyl substituted with 0-5 occurrencesof R^(d).

In some embodiments, R¹ is tetrahydrofuranyl substituted with 0-5occurrences of R^(d)(e.g., 2-tetrahydrofuranyl or 3-tetrahydrofuranyl).In some aspects of these embodiments, R¹ is tetrahydrofuranyl (e.g.,2-tetrahydrofuranyl or 3-tetrahydrofuranyl). In some aspects of theseembodiments, L is —C(O)—.

In some embodiments, R¹ is azetidinyl substituted with 0-5 occurrencesof R^(d) (e.g., 3-azetidinyl). In some embodiments, R¹ is azetidinyl(e.g., 3-azetidinyl). In some embodiments, R¹ is azetidinyl (e.g.,3-azetidinyl) substituted with 1 occurrence of R^(d). In some aspects ofthese embodiments, R^(d) is alkyl (e.g., methyl or ethyl). In someaspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is 10-14 membered bicyclic aryl substituted with0-5 occurrences of R^(d). In some embodiments, R^(d) is naphthylsubstituted with 0-5 occurrences of R^(d). In some embodiments, R^(d) isnaphthyl.

In some embodiments, L is a bond, —(CR^(c)R^(c))_(m)—, —NR^(b)C(O)—,—(CR^(c)R^(c))_(m)—C(O)—, —C(O)—, or —O(CO)—.

In some embodiments, L is a bond and R¹ is alkyl, aryl or heteroarylsubstituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, alkyl, aryl or heteroaryl of R¹ is as described in any oneof the embodiments and aspects above.

In some embodiments, L is —(CR^(c)R^(c))_(m)— and R¹ is cycloalkyl,aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences ofR^(d). In some aspects of these embodiments, cycloalkyl, aryl,heteroaryl or heterocyclyl of R¹ is as described in any one of theembodiments and aspects above.

In some embodiments, L is —NR^(b)C(O)— and R^(b) is hydrogen; and R¹ isaryl substituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, aryl of R¹ is as described in any one of the embodimentsand aspects above.

In some embodiments, L is —(CR^(c)R^(c))_(m)—C(O)— and R¹ is cycloalkyl,aryl or heteroaryl substituted with 0-5 occurrences of R^(d). In someaspects of these embodiments, cycloalkyl, aryl, or heteroaryl of R¹ isas described in any one of the embodiments and aspects above.

In some embodiments, L is —C(O)— and R¹ is aryl, alkyl, or heteroarylsubstituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, aryl, alkyl, or heteroaryl of R¹ is as described in any oneof the embodiments and aspects above.

In some embodiments, L is —OC(O)— and R¹ is alkyl, aryl or heterocyclylsubstituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, alkyl, aryl, or heterocyclyl of R¹ is as described in anyone of the embodiments and aspects above.

In some embodiments, L is —(CR^(c)R^(c))_(m)—OC(O)— and R¹ isheterocyclyl or cycloalkyl substituted with 0-5 occurrences of R^(d). Insome aspects of these embodiments, heterocyclyl or cycloalkyl of R¹ isas described in any one of the embodiments and aspects above.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, R³ is alkyl (e.g., methyl or ethyl). In someembodiments, R³ is —OR^(a). In some aspects of these embodiments, R^(a)is alkyl (e.g., methyl or ethyl). In some embodiments, R³ is halo (e.g.,fluorine or chlorine). In some embodiments, R³ is hydroxyl. In someembodiments, R³ is haloalkyl (e.g., trifluoromethyl).

In some embodiments, n is 2.

In some embodiments, two adjacent R³ taken together with the carbonatoms to which they are attached form a heterocyclyl ring. In someembodiments, both R³ are —OR^(a). In some embodiments, two adjacent R³taken together with the carbon atoms to which they are attached form

In certain embodiments, a compound is of formula (II) or apharmaceutical acceptable salt thereof:

wherein L, R¹, R³, R^(a), R^(b), R^(c), R^(d), Y, Z, m, h and g are asdefined above in formula (I) or any one of the embodiments or aspectsdescribed herein.

In certain embodiments, A is aryl (e.g., phenyl or naphthyl) optionallysubstituted with 1 or 2 occurrences of R², wherein each R² isindependently selected from halo, haloalkyl, aryl, heteroaryl, alkyl,—OR^(a), —COOR^(c), or —CONR^(c)R^(c); and D, D¹, L, R¹, R³, R^(a),R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined above informula (I) or any one of the embodiments or aspects described herein.In some aspect of these embodiments, D and D¹ are N. In some aspect ofthese embodiments, at least one of W, X, Y and Z is N. In some aspect ofthese embodiments, one of W, Y and Z is N; h is 1 and g is 1.

In certain embodiments, A is heteroaryl (e.g., N-containing monocyclicheteroaryl or N-containing bicyclic heteroaryl); and D, D¹, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as definedabove in formula (I) or any one of the embodiments or aspects describedherein. In some embodiments, A is a 5-8 membered monocyclic heteroaryl(e.g., pyridyl, pyrimidyl, or pyrazyl); and D, D¹, L, R¹, R³, R^(a),R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined above informula (I) or any one of the embodiments or aspects described herein.In some embodiments, A is a 5-8 membered N-containing monocyclicheteroaryl; and D, D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z,W, n, m, h and g are as defined above in formula (I) or any one of theembodiments or aspects described herein. In some embodiments, A isoptionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl or4-pyridyl), optionally substituted pyrimidyl (e.g., 2-pyrimidyl or5-pyrimidyl), or optionally substituted pyrazyl (e.g., 2-pyrazyl); andL, R¹, R³, R^(a), R^(b), R^(c), R^(d), Y, Z, m, h and g are as definedabove in formula (I) or any one of the embodiments or aspects describedherein.

In some embodiments, A is substituted with 1 occurrence of R²; and D,D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g areas defined above in formula (I) or any one of the embodiments or aspectsdescribed herein. In some aspects of these embodiments, R² is alkyl(e.g., methyl or ethyl). In some aspects of these embodiments, R² ishalo. In some aspects of these embodiments, R² is fluorine (F). In someaspects of these embodiments, R² is bromine (Br). In some aspects ofthese embodiments, R² is chlorine (Cl). In some aspects of theseembodiments, R² is —OR^(a). In some aspects of these embodiments, R^(a)is alkyl (e.g., methyl).

In some embodiments, A is substituted with 2 occurrences of R²; and D,D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g areas defined above in formula (I) or any one of the embodiments or aspectsdescribed herein. In some aspects of these embodiments, both R² are halo(e.g., fluorine or fluorine and chlorine). In some aspects of theseembodiments, both R² are alkyl (e.g, methyl). In some aspects of theseembodiments, both R² are —OR^(a). In some aspects of these embodiments,one R² is halo and the other is —OR^(a). In some aspects of theseembodiments, one R² is bromine (BR) and the other is —OR^(a). In someaspects of these embodiments, one R² is chlorine (Cl) and the other is—OR^(a). In some aspects of these embodiments, one R² is fluorine (F)and the other is —OR^(a). In some aspects of these embodiments, R^(a) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments,both R² are —OR^(a). In some aspects of these embodiments, two —OR^(a)taken together with the carbon atoms to which they are attached form aheterocyclyl. In some embodiments, A is

and D, D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, hand g are as defined above in formula (I) or any one of the embodimentsor aspects described herein.

In another embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—, or —C(O)NR^(b)—;

R¹ is independently selected from alkyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl; each of which are substituted with 0-3 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a) or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted cyclyl;

each R^(a) is independently selected from alkyl and haloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, alkyl, nitro,cyano and —OR^(a), or two R^(d) taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2. In some aspects of this embodiment, A, D, D¹, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined inany one of the embodiments or aspects described herein.

In another embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(c);

A is optionally substituted aryl or optionally substituted heteroaryl;

R¹ is independently selected from alkyl, optionally substituted aryl,and optionally substituted heteroaryl;

each R³ is independently selected from halo, haloalkyl, alkyl, and—OR^(a);

each R^(a) is independently selected from alkyl, haloalkyl andoptionally substituted heteroaryl;

each R^(b) is independently alkyl;

each R^(c) is independently selected from hydrogen or alkyl;

n is 0, 1, or 2;

h is 0, 1, 2; and

g is 0, 1 or 2. In some aspects of this embodiment, A, D, D¹, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined inany one of the embodiments or aspects described herein.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Ib) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ib):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Z, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In some embodiments, X, W and Z are CH. In some embodiments, one of X, Wand Z is N and the other two of X, W and Z are CH.

In another embodiment, provided is a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ic) or a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt of formula (Ic):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Y, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In some embodiments, X, Y and W are CH. In some embodiments, one of X, Yand W is N and the other two of X, Y and W are CH.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Id) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Id):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), Y, Z, m, h and g areas defined above in formula (I) or any one of the embodiments or aspectsdescribed herein.

In some embodiments, Y and Z are CH. In some embodiments, one of Y and Zis N and one of Y and Z is CH.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Ie) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ie):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Y, Z, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In certain embodiments, exemplary compounds of Formula I include thecompounds described in FIG. 1 and in the Examples.

Compounds described herein are useful as activators of PKR mutantshaving lower activities compared to the wild type, thus are useful formethods of the present invention. Such mutations in PKR can affectenzyme activity (catalytic efficiency), regulatory properties(modulation by fructose bisphosphate (FBP)/ATP), and/or thermostabilityof the enzyme. Examples of such mutations are described in Valentini etal, JBC 2002. Some examples of the mutants that are activated by thecompounds described herein include G332S, G364D, T384M, G37E, R479H,R479K, R486W, R532W, R510Q, and R490W. Without being bound by theory,compounds described herein affect the activities of PKR mutants byactivating FBP non-responsive PKR mutants, restoring thermostability tomutants with decreased stability, or restoring catalytic efficiency toimpaired mutants. The activating activity of the present compoundsagainst PKR mutants may be tested following a method described inExample 1. Compounds described herein are also useful as activators ofwild type PKR.

In an embodiment, to increase the lifetime of the red blood cells, acompound, composition or pharmaceutical composition described herein isadded directly to whole blood or packed cells extracorporeally or beprovided to the patient directly (e.g., by i.p., i.v., i.m., oral,inhalation (aerosolized delivery), transdermal, sublingual and otherdelivery routes). Without being bound by theory, compounds describedherein increase the lifetime of the RBCs, thus counteract aging ofstored blood, by impacting the rate of release of 2,3-DPG from theblood. A decrease in the level of 2, 3-DPG concentration induces aleftward shift of the oxygen-hemoglobin dissociation curve and shiftsthe allosteric equilibribrium to the R, or oxygenated state, thusproducing a therapeutic inhibition of the intracellular polymerizationthat underlies sickling by increasing oxygen affinity due to the 2,3-DPGdepletion, thereby stabilizing the more soluble oxy-hemoglobin.Accordingly, in one embodiment, compounds and pharmaceuticalcompositions described herein are useful as antisickling agents. Inanother embodiment, to regulate 2,3-diphosphoglycerate, a compound,composition or pharmaceutical composition described herein is addeddirectly to whole blood or packed cells extracorporeally or be providedto the patient directly (e.g., by i.p., i.v., i.m., oral, inhalation(aerosolized delivery), transdermal, sublingual and other deliveryroutes).

A compound described herein may be an activator of a PKR, for example, awild type (wt) or mutated PKR (e.g., R510Q, R532W, OR T384W). Exemplarycompounds are shown in FIG. 1. As shown in FIG. 1, A refers to acompound that has a % activation at 1 μM of from 1 to 100. B refers toan a compound that has a % activation at 1 μM of from 101 to 500. Crefers a compound that has a % activation at 1 μM of >500.

In FIG. 1, a compound described herein may also have an AC50 of wildtype PKR, PKR R532W, PKR T384W, PKR G332S, PKR G364D, PKR G37E and/orPKR R479H. AA refers to an AC50 less than 100 nM, BB refers to an AC50from 101 nM to 500 nM and CC refers to an AC50 greater than 500 nM.

Other exemplary compounds can be found in International PatentApplication No. PCT/US2010/040486 (e.g., in FIG. 1), published as WO2011/002817 which is incorporated herein by reference in its entirety.

The compounds described herein can be made using a variety of synthetictechniques.

Scheme 1 above is an exemplary scheme that depicts a representativesynthesis of certain compounds described herein. Sulfonyl chloride 1 isreacted with amine 2 under standard coupling conditions to produce ester3. Hydrolysis of 3 using lithium hydroxide generates carboxylic acid 4.Piperazine (5) is with the appropriate bromide under standard palladiumcoupling conditions to provide 7. Carboxylic acid 4 is then treated withpiperazine derivative 7 to produce final compound 8.

The compounds described herein can be made using procedures disclosed inInternational Patent Application No. PCT/US2010/040486, published as WO2011/002817 which is incorporated herein by reference in its entirety.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Additionally, the various synthetic steps maybe performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds provided herein may contain one or more asymmetric centersand thus occur as racemates and racemic mixtures, single enantiomers,individual diastereomers and diastereomeric mixtures. All such isomericforms of these compounds are expressly included within the scope. Unlessotherwise indicated when a compound is named or depicted by a structurewithout specifying the stereochemistry and has one or more chiralcenters, it is understood to represent all possible stereoisomers of thecompound. The compounds provided herewith may also contain linkages(e.g., carbon-carbon bonds) or substituents that can restrict bondrotation, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded.

The compounds provided herein (e.g. of Formula I) may also comprise oneor more isotopic substitutions. For example, H may be in any isotopicform, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may bein any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in anyisotopic form, including ¹⁶O and ¹⁸O; and the like. The compoundsprovided herein may also be represented in multiple tautomeric forms, insuch instances, expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented (e.g., alkylation of a ring system may result in alkylationat multiple sites; all such reaction products are expressly included).All such isomeric forms of such compounds are expressly included. Allcrystal forms of the compounds described herein are expressly included.

The compounds provided herein include the compounds themselves, as wellas their salts and their prodrugs, if applicable. A salt, for example,can be formed between an anion and a positively charged substituent(e.g., amino) on a compound described herein. Suitable anions includechloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt canalso be formed between a cation and a negatively charged substituent(e.g., carboxylate) on a compound described herein. Suitable cationsinclude sodium ion, potassium ion, magnesium ion, calcium ion, and anammonium cation such as tetramethylammonium ion. Examples of prodrugsinclude esters and other pharmaceutically acceptable derivatives, which,upon administration to a subject, are capable of providing activecompounds.

The compounds provided herein may be modified by appending appropriatefunctionalities to enhance selected biological properties, e.g.,targeting to a particular tissue. Such modifications are known in theart and include those which increase biological penetration into a givenbiological compartment (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁-C₁₂ alkyl indicates that the group may have from1 to 12 (inclusive) carbon atoms in it. The term “haloalkyl” refers toan alkyl in which one or more hydrogen atoms are replaced by halo, andincludes alkyl moieties in which all hydrogens have been replaced byhalo (e.g., perfluoroalkyl). The terms “arylalkyl” or “aralkyl” refer toan alkyl moiety in which an alkyl hydrogen atom is replaced by an arylgroup. Aralkyl includes groups in which more than one hydrogen atom hasbeen replaced by an aryl group. Examples of “arylalkyl” or “aralkyl”include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl,and trityl groups.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent. The term “alkynyl” refers to a straight or branchedhydrocarbon chain containing 2-12 carbon atoms and characterized inhaving one or more triple bonds. Examples of alkynyl groups include, butare not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triplebond carbons may optionally be the point of attachment of the alkynylsubstituent.

The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and—NH(alkyl)₂ radicals respectively. The term “aralkylamino” refers to a—NH(aralkyl) radical. The term alkylaminoalkyl refers to a(alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a(alkyl)₂N-alkyl- radical The term “alkoxy” refers to an —O-alkylradical. The term “mercapto” refers to an SH radical. The term“thioalkoxy” refers to an —S-alkyl radical. The term thioaryloxy refersto an —S-aryl radical.

The term “aryl” refers to a monocyclic, bicyclic, or tricyclic aromatichydrocarbon ring system, wherein any ring atom capable of substitutioncan be substituted (e.g., by one or more substituents). Examples of arylmoieties include, but are not limited to, phenyl, naphthyl, andanthracenyl.

The term “cycloalkyl” as employed herein includes cyclic, bicyclic,tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12carbons. Any substitutable ring atom can be substituted (e.g., by one ormore substituents). The cycloalkyl groups can contain fused or spirorings. Fused rings are rings that share a common carbon atom. Examplesof cycloalkyl moieties include, but are not limited to, cyclopropyl,cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to14-membered non-aromatic ring structures (e.g., 3- to 14-membered rings,more preferably 3- to 7-membered rings), whose ring structures includeone to four heteroatoms independently selected from O, N and S. Theheterocyclyl or heterocyclic groups can contain fused or spiro rings.Heterocycles can also be polycycles, with each group having, e.g., 5-7ring members. The term “heterocyclyl” or “heterocyclic group” includessaturated and partially saturated heterocyclyl structures. The term“heteroaryl” refers to a 5-14 membered (i.e., a 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic) aromatic ringsystem having 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatomsif bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring heteroatomsindependently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 ringheteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively). Any substitutable ring atom can be substituted (e.g., byone or more substituents). Heterocyclyl and heteroaryl groups include,for example, thiophene, thianthrene, furan, pyran, isobenzofuran,chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole,isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, pyrimidine, phenanthroline, phenazine, phenarsazine,phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane,oxazole, piperidine, piperazine, morpholine, lactones, lactams such asazetidinones and pyrrolidinones, sultams, sultones, and the like. Theheterocyclic or heteroaryl ring can be substituted at one or morepositions with such substituents as described herein, as for example,halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino,nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN,or the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “cycloalkenyl” refers to partially unsaturated, nonaromatic,monocyclic, bicyclic, or tricyclic hydrocarbon groups having 5 to 12carbons, preferably 5 to 8 carbons. The unsaturated carbon mayoptionally be the point of attachment of the cycloalkenyl substituent.Any substitutable ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkenyl groups can contain fused or spiro rings.Fused rings are rings that share a common carbon atom. Examples ofcycloalkenyl moieties include, but are not limited to, cyclohexenyl,cyclohexadienyl, or norbornenyl.

The term “heterocycloalkenyl” refers to a partially saturated,nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms independently selected from O, N, and S (e.g., 1-3, 1-6, or1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, ortricyclic, respectively). The unsaturated carbon or the heteroatom mayoptionally be the point of attachment of the heterocycloalkenylsubstituent. Any substitutable ring atom can be substituted (e.g., byone or more substituents). The heterocycloalkenyl groups can containfused rings. Fused rings are rings that share a common carbon atom.Examples of heterocycloalkenyl include but are not limited totetrahydropyridyl and dihydropyranyl.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group. The ring heteroatoms ofthe compounds provided herein include N—O, S(O), and S(O)₂.

The term “oxo” refers to an oxygen atom, which forms a carbonyl whenattached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted (e.g., by one or moresubstituents).

The term “substituents” refers to a group “substituted” on an alkyl,cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any substitutable atom ofthat group. Any substitutable atom can be substituted. Unless otherwisespecified, such substituents include, without limitation, alkyl (e.g.,C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 straight or branchedchain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF₃),aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl,alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g.,perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate,cyano, nitro, amino, alkyl amino, SO₃H, sulfate, phosphate,methylenedioxy (—O—CH₂—O— wherein oxygens are attached to vicinalatoms), ethylenedioxy, oxo (not a substituent on heteroaryl), thioxo(e.g., C═S) (not a substituent on heteroaryl), imino (alkyl, aryl,aralkyl), S(O)_(n)alkyl (where n is 0-2), S(O)_(n) aryl (where n is0-2), S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n) heterocyclyl (wheren is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl,aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide(mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof).In one aspect, the substituents on a group are independently any onesingle, or any subset of the aforementioned substituents. In anotheraspect, a substituent may itself be substituted with any one of theabove substituents.

The term “activator” as used herein means an agent that (measurably)increases the activity of wild type pyruvate kinase R (wtPKR) or causeswild type pyruvate kinase R (wt PKR) activity to increase to a levelthat is greater than wt PKR's basal levels of activity or an agent that(measurably) increases the activity of a mutant pyruvate kinase R (mPKR)or causes mutant pyruvate kinase R (mPKR) activity to increase to alevel that is greater than that mutant PKR's basal levels of activity,for examples, to a level that is 20%, 40%, 50%, 60%, 70%, 80%, 90% or100% of the activity of wild type PKR.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

Certain activator compounds useful as PKR wild type and/or mutantactivators are those that demonstrate specificity and activation of PKRenzyme (wild type and/or a mutant enzyme) in the absence of FBP to alevel greater than that of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 99, or 100% in the presence of FBP.

Methods of Treatment

In one embodiment, provided is a method for treating or preventing adisease, condition or disorder as described herein (e.g., treating)comprising administering a compound, a pharmaceutically acceptable saltof a compound or pharmaceutical composition comprising a compounddescribed herein (e.g., a compound of formula (I), (I-a), (II) or inFIG. 1).

The compounds and compositions described herein can be administered tocells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., invivo, to treat, prevent, and/or diagnose a variety of disorders,including those described herein below.

As used herein, the term “treat” or “treatment” is defined as theapplication or administration of a compound, alone or in combinationwith, a second compound to a subject, e.g., a patient, or application oradministration of the compound to an isolated tissue or cell, e.g., cellline, from a subject, e.g., a patient, who has a disorder (e.g., adisorder as described herein), a symptom of a disorder, or apredisposition toward a disorder, with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisorder, one or more symptoms of the disorder or the predispositiontoward the disorder (e.g., to prevent at least one symptom of thedisorder or to delay onset of at least one symptom of the disorder).

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, an amount of a compound effective to prevent a disorder,or a “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein or a normalsubject. The term “non-human animals” includes all vertebrates, e.g.,non-mammals (such as chickens, amphibians, reptiles) and mammals, suchas non-human primates, domesticated and/or agriculturally usefulanimals, e.g., sheep, dog, cat, cow, pig, etc.

Compositions and Routes of Administration

The compositions delineated herein include the compounds delineatedherein (e.g., a compound described herein), as well as additionaltherapeutic agents if present, in amounts effective for achieving amodulation of disease or disease symptoms, including those describedherein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound provided herewith, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions provided herewith include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions provided herewith may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions provided herewith may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions provided herewith may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions provided herewith may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound providedherewith with a suitable non-irritating excipient which is solid at roomtemperature but liquid at the rectal temperature and therefore will meltin the rectum to release the active components. Such materials include,but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions provided herewith may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

When the compositions provided herewith comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds provided herewith. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds providedherewith in a single composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositionsprovided herewith will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination provided herewith may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Patient Selection and Monitoring

The compounds described herein can activate mutant PKRs. Accordingly, apatient and/or subject can be selected for treatment using a compounddescribed herein by first evaluating the patient and/or subject todetermine whether the subject carries a mutation in PKR (for examples,one of the mutations as described herein), and if the subject isdetermined to be carrying a mutation in PKR thus is in need ofactivation of the activity of the mutant PKR, then optionallyadministering to the subject a compound described herein. A subject canbe evaluated as carrying a mutation in PKR using methods known in theart.

EXAMPLES Example 1. PKR Mutant Assay

Procedure:

-   -   PKR or PKR mutant enzyme solution was diluted in assay buffer.    -   2 μL of test compound was added into wells first, and then 180        μL reaction mix was added.    -   Reactions mixture with test compound was assembled except for        ADP, and plates were stored for 60 minutes at room temperature.    -   20 uL ADP was added to start reaction at room temperature and        reaction progress was measured as changes in absorbance at 340        nm wavelength at room temperature.

Test Compound Preparation:

-   -   Test compound stock was made at 100× concentration in 100% DMSO        (10 mM)    -   1 to 3 dilutions were made for 11 points (i.e. 50 μl of first        concentration added to 100 μl 100% DMSO to yield 3.33 mM, 50 μl        of this added to 100 μl DMSO to yield 1.11 mM, and so forth)    -   1 to 100 dilution into assay (2 μl in 200 μl) yielded starting        concentration of 100 μM, decreasing 3 fold for 11 points.        Assay Buffer: 100 mM KCl, 50 mM Tris 7.5, 5 mM MgCl2, 1 mM DTT,        0.03% BSA        Reaction Mixture: PKR mutant enzyme: 80-400 ng/well; ADP:        0.22-1.65 mM; PEP: 0.1-0.5 mM; NADH: 180 uM; LDH: 0.5 units        (Sigma#59023); DTT: 1 mM; BSA: 0.03%.

Representative compounds disclosed herein were tested to be an activatorof wild type PKR, PKRR532W, PKRR479H, and PKRG332S with an AC50 lessthan 500 nM against each wild type/mutant enzyme.

Example 2. PKR WT Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final concentration: PKR wt (100 ng/well), Tris pH 7.5 (50 mM), KCl (100mM), MgCl₂ (5 mM), ADP (0.48 mM), PEP (0.15 mM), NADH (180 μM), LDH (0.5units, Sigma 59023), DTT (1 mM) and BSA (0.03%).

Example 3. PKR R510Q Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final concentration: PKR R510Q (40 ng/well), Tris pH 7.5 (50 mM), KCl(100 mM), MgCl₂ (5 mM), ADP (0.2 mM), PEP (0.11 mM), NADH (180 μM), LDH(0.5 units, Sigma 59023), DTT (1 mM) and BSA (0.03%).

Example 4. PKR R532W Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final concentration: PKR R532W (100 ng/well), Tris pH 7.5 (50 mM), KCl(100 mM), MgCl2 (5 mM), ADP (0.36 mM), PEP (0.1 mM), NADH (180 μM), LDH(0.5 units, Sigma 59023), DTT (1 mM) and BSA (0.03%).

Example 5. PKR T384W Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL enzyme solution was added.Assays were assembled except for ADP, and plates were stored for 60minutes at RT. 20 μL ADP was added to start the assay and assay outputwas evaluated using OD340 at SpectraMax. The assay was run at roomtemperature.

Final concentration: PKR T384W soluble (300 ng/well), Tris pH 7.5 (50mM), KCl (100 mM), MgCl2 (5 mM), ADP (0.08 mM), PEP (0.23 mM), NADH (180μM), LDH (0.5 units, Sigma 59023), DTT (1 mM) and BSA (0.03%).

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

What is claimed is:
 1. A method of activating a mutant pyruvate kinase Rin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:

W, X, Y and Z are each independently selected from CH or N; D and D¹ areeach independently selected from a bond and NR^(b); A is an optionallysubstituted aryl or an optionally substituted heteroaryl; L is a bond,—C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—, —(CR^(c)R^(c))_(m)—OC(O)—,—(CR^(c)R^(c))_(m)—C(O)—, —NR^(b)C(S)—, or —NR^(b)C(O)— (wherein thepoint of the attachment to R¹ is on the left-hand side); R¹ is selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each ofwhich is substituted with 0-5 occurrences of R^(d); each R³ isindependently selected from halo, haloalkyl, alkyl, hydroxyl and—OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl; each R^(b) is independently selected from hydrogen and alkyl;each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy, or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl; eachR^(d) is independently selected from halo, haloalkyl, haloalkoxy, alkyl,alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a), —C(O)OR^(a),—SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) taken together with thecarbon atoms to which they are attached form an optionally substitutedheterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 0, 1, 2; and g is 0,1 or
 2. 2. The method of claim 1, wherein h is 1 and g is
 1. 3. Themethod of claim 2, wherein W, X, Y and Z are CH.
 4. The method of claim3, wherein D is NR^(b) and D¹ is a bond.
 5. The method of claim 4,wherein R^(b) is H, methyl or ethyl.
 6. The method of claim 5, wherein Lis a bond, —(CR^(c)R^(c))_(m)—, —NR^(b)C(O)—, —(CR^(c)R^(c))_(m)—C(O)—,—C(O)—, or —O(CO)—.
 7. The method of claim 6, wherein L is—(CR^(c)R^(c))_(m)—.
 8. The method of claim 7, wherein R is cycloalkyl,aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences ofR^(d).
 9. The method of claim 7, wherein R¹ is cycloalkyl.
 10. Themethod of claim 9, wherein L is —CH₂— and n is
 0. 11. The method ofclaim 1, wherein A is quinolinyl.
 12. The method of claim 1, wherein Ais


13. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof is selected from:


14. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


15. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


16. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


17. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


18. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


19. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


20. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


21. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


22. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


23. The method of claim 1, wherein the compound or a pharmaceuticallyacceptable salt thereof has the structural formula:


24. The method of claim 1, wherein the mutant PKR is selected fromG332S, G364D, T384M, R479H, R479K, R486W, R532W, R510Q, and R490W.